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【结 构 式】 
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【分子编号】27739 【品名】2-bromoaniline 【CA登记号】615-36-1 |
【 分 子 式 】C6H6BrN 【 分 子 量 】172.02438 【元素组成】C 41.89% H 3.52% Br 46.45% N 8.14% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 2-bromo-p-toluidine (I) with cyclohexane-1,3-dione (II) gives bromo enaminone (III), which is N-methylated with iodomethane and NaH, affording tertiary enaminone (IV). Treatment of (IV) with triphenylphosphine-palladium acetate complex/NHCO3 or palladium acetate in acetonitrile provides carbazolone (V). Treatment of carbazolone (V) with sodium metal in EtOH/dioxane (or sodium methoxide in 1,2-dimethoxyethane) and diethyl oxalate (VI) provides ethoxallyl derivative (VII), which is then converted into glyoxylic acid lactone (VIII). Coupling of (VIII) with 2-methylimidazol (IX) by means of benzyltriethylammonium chloride in CHCl3/H2O furnishes glyoxylate (X), which is converted into the target product by reaction again with 2-methylimidazol (IX) in dioxane and final treatment with HCl. Alternatively, glyoxylate (X) can be directly obtained from (VIII) by reaction with formaldehyde and 2-methylimidazol (IX) in dioxane.
| 【1】 Iida, H.; et al.; Intramolecular cyclization of enaminones involving arylpalladium complexes. Synthesis of carbazoles. J Org Chem 1980, 45, 15, 2938. |
| 【2】 Harsanyi, K.; Bod, P.; Trischler, F.; Fekecs, E.; Horvath, E.; Csehl, A.; Hegedus, B.; Mersich, E.; Szabo, G. (Gedeon Richter Ltd.); Carbazolone derivs. and process for preparing the same. EP 0595111 . |
| 【3】 Dobay, L.; Czibula, L.; Szantay, C.; Gazdag, M.; Greiner, I.; Werkne Papp, E.; Tarkanyi, G.; Zsoldosne Babjak, M.; Mihalyfi, K. (Gedeon Richter Ltd.); An intermediate and process for its synthesis. WO 0172716 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (II) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (III) | 53887 | 3-(2-bromoanilino)-2-cyclohexen-1-one | n/a | C12H12BrNO | 详情 | 详情 |
| (IV) | 53888 | 3-[2-bromo(methyl)anilino]-2-cyclohexen-1-one | n/a | C13H14BrNO | 详情 | 详情 |
| (V) | 53889 | 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one | 27387-31-1 | C13H13NO | 详情 | 详情 |
| (VI) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VII) | 53890 | ethyl 2-hydroxy-2-(9-methyl-4-oxo-1,2,4,9-tetrahydro-3H-carbazol-3-ylidene)acetate | n/a | C17H17NO4 | 详情 | 详情 |
| (VIII) | 53891 | n/a | C16H13NO4 | 详情 | 详情 | |
| (IX) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (X) | 53892 | 2-methyl-1H-imidazol-3-ium 2-[3-(hydroxymethyl)-9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-oxoacetate | n/a | C20H21N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Suzuki coupling of 2-bromoaniline (I) with boronic acid (II) in the presence of a palladium catalyst gave biphenyl (III). Subsequent condensation of (III) with ethyl acetoacetate (IV) afforded enamine (V), which was cyclized to hydroxyquinoline (VI) in refluxing diphenyl ether. Chlorination of (VI) in boiling POCl3 produced the corresponding 4-chloroquinoline (VII). This was finally condensed with N-(cyclopropylmethyl)-N--propylamine (VIII) to provide the target aminoquinoline.
| 【1】 Huang, C.; Chen, C.; McCarthy, J.R.; Haddach, M.; Wilcoxen, K.M. (Janssen Pharmaceutica NV; Neurocrine Biosciences Inc.); CRF antagonistic quino- and quinazolines. EP 0977737; WO 9847874 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (II) | 27740 | mesitylboronic acid | 5980-97-2 | C9H13BO2 | 详情 | 详情 |
| (III) | 27741 | 2',4',6'-trimethyl[1,1'-biphenyl]-2-amine | C15H17N | 详情 | 详情 | |
| (IV) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (V) | 27742 | ethyl (E)-3-(2-mesitylanilino)-2-butenoate | C21H25NO2 | 详情 | 详情 | |
| (VI) | 27743 | 8-mesityl-2-methyl-4-quinolinol | C19H19NO | 详情 | 详情 | |
| (VII) | 27744 | 4-chloro-8-mesityl-2-methylquinoline | C19H18ClN | 详情 | 详情 | |
| (VIII) | 27745 | N-(cyclopropylmethyl)-1-propanamine | 26389-60-6 | C7H15N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)2-Bromoaniline (VIII) is acylated by bromoacetyl chloride (IX) in pyridine to produce the corresponding bromoacetanilide (X). Subsequent displacement of the aliphatic bromide of (X) with morpholine (XI) furnishes the morpholinoacetanilide (XII). Alkylation at the amide N of (XII) with iodomethane and NaH leads to the N-methyl amide (XIII). Stille coupling of aryl bromide (XIII) with tributyl (1-ethoxyvinyl)tin (XIV) yields the enol ether (XV). Bromination of enol ether (XV) with N-bromosuccinimide in moist THF produces the bromo acetophenone (XVI), which is further reacted with NaN3 to give the azido ketone (XVII). The target amino oxazole compound is finally obtained by condensation of azido ketone (XVII) with isothiocyanate (VII) in the presence of PPh3 in hot dioxane.
| 【1】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 | |
| (VIII) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (X) | 61698 | 2-bromo-N-(2-bromophenyl)acetamide | C8H7Br2NO | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XII) | 61699 | N-(2-bromophenyl)-2-(4-morpholinyl)acetamide | C12H15BrN2O2 | 详情 | 详情 | |
| (XIII) | 61700 | N-(2-bromophenyl)-N-methyl-2-(4-morpholinyl)acetamide | C13H17BrN2O2 | 详情 | 详情 | |
| (XIV) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (XV) | 61850 | N-[2-(1-ethoxyvinyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C17H24N2O3 | 详情 | 详情 | |
| (XVI) | 61851 | N-[2-(2-bromoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C15H19BrN2O3 | 详情 | 详情 | |
| (XVII) | 61852 | N-[2-(2-azidoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C15H19N5O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)In a related synthetic strategy, acylation of 2-bromoaniline (I) with acetoxyacetyl chloride (II) affords the acetoxy acetanilide (III). Alkylation of amide (III) with iodomethane and NaH leads to the N-methyl amide (IV). Then, Stille coupling of aryl bromide (IV) with tributyl (1-ethoxyvinyl)tin (V) gives rise to the enol ether (VI). Bromination of (VI) with N-bromosuccinimide in moist THF, followed by displacement of the resultant bromo ketone (VII) with NaN3 provides azido ketone (VIII). The key oxazole (X) is then obtained by condensation of azido ketone (VIII) with isothiocyanate (IX) in the presence of PPh3. Alkaline hydrolysis of the acetate ester (X) yields alcohol (XI), which is converted to mesylate (XII) by means of methanesulfonyl chloride and triethylamine. The mesylate group is finally displaced with morpholine (XIII) to furnish the title compound.
| 【1】 Dhar, T.G.M.; Guo, J.; Shen, Z.; et al.; A modified approach to 2-(N-aryl)-1,3-oxazoles: application to the synthesis of the IMPDH inhibitor BMS-337197 and analogues. Org Lett 2002, 4, 12, 2091. |
| 【2】 Dhar, T.G.M.; et al.; Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]-amino]-5-oxazolyl]phenyl]-N-methyl-4-morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity. J Med Chem 2002, 45, 11, 2127. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (II) | 10456 | Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate | 13831-31-7 | C4H5ClO3 | 详情 | 详情 |
| (III) | 61853 | 2-(2-bromoanilino)-2-oxoethyl acetate | C10H10BrNO3 | 详情 | 详情 | |
| (IV) | 61854 | 2-[2-bromo(methyl)anilino]-2-oxoethyl acetate | C11H12BrNO3 | 详情 | 详情 | |
| (V) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (VI) | 61855 | 2-[2-(1-ethoxyvinyl)(methyl)anilino]-2-oxoethyl acetate | C15H19NO4 | 详情 | 详情 | |
| (VII) | 61856 | 2-[2-(2-bromoacetyl)(methyl)anilino]-2-oxoethyl acetate | C13H14BrNO4 | 详情 | 详情 | |
| (VIII) | 61857 | 2-[2-(2-azidoacetyl)(methyl)anilino]-2-oxoethyl acetate | C13H14N4O4 | 详情 | 详情 | |
| (IX) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 | |
| (X) | 61858 | 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl acetate | C24H22N4O6 | 详情 | 详情 | |
| (XI) | 61859 | 2-hydroxy-N-(2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}phenyl)-N-methylacetamide | C22H20N4O5 | 详情 | 详情 | |
| (XII) | 61860 | 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl methanesulfonate | C23H22N4O7S | 详情 | 详情 | |
| (XIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III). This is condensed with ethyl acetoacetate (IV) to produce enamine (V), which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI). Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII). Finally, displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound
| 【1】 Nakazato, A.; et al.; Chemical modification of 4-carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine, CRA0316, for discovery CRH1 receptor antagonists. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Kennis, L.; Kumagai, T.; Nakazato, A.; et al.; Synthesis, SAR and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinoquinoline derivative. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 258. |
| 【3】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (II) | 48912 | 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid | 68716-47-2 | C6H5BCl2O2 | 详情 | 详情 |
| (III) | 60295 | 2',4'-dichloro[1,1'-biphenyl]-2-amine; 2',4'-dichloro[1,1'-biphenyl]-2-ylamine | C12H9Cl2N | 详情 | 详情 | |
| (IV) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (V) | 60296 | ethyl 3-[(2',4'-dichloro[1,1'-biphenyl]-2-yl)amino]-2-butenoate | C18H17Cl2NO2 | 详情 | 详情 | |
| (VI) | 60297 | 8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol | C16H11Cl2NO | 详情 | 详情 | |
| (VII) | 60298 | 8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl trifluoromethanesulfonate | C17H10Cl2F3NO3S | 详情 | 详情 | |
| (VIII) | 60299 | 1,2,3,6-tetrahydro-4-pyridinecarboxamide | C6H10N2O | 详情 | 详情 |